Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Our previous work has demonstrated that the Sezary form, or typically leukemic form of CTCL, is characterized by prominent immunologic defects including depressed cell-mediated immunity. We have also demonstrated increased production of T-helper type 2 (Th2) cytokines (IL-4, IL-5) and deficient production of Th1 cytokines (IL-2 and interferon gamma [IFN gamma]) by their peripheral blood cells (PBMC) as well as detecting IL-4 and IL-5 mRNA within lesional skin but not normal skin of patients with all stages of CTCL. A marked defect in IL-12 production in CTCL has also been noted, which may also play a role in depressed cell-mediated immunity. Because evidence exists for an antitumor T-cell response and since IL-12 is pivotal in stimulating cytotoxic T-cells, we have completed a phase I trial of IL-12 conducted in our GCRC to treat CTCL. Our data indicate that IL-12 has marked therapeutic activity. This K24 translational grant should permit the P.I. greater time to focus on understanding the in vivo mechanisms of action of IL-12 and other therapeutically active cytokines by studying 1) skin immune cells, 2) cytokine expression, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression. We will also characterize the effects of IL- 12 to inhibit growth and induce apoptosis of the purified malignant CD4+ T-cells and determine if there is in vitro synergism with the therapeutically active agent, IFN alpha. We will also examine IL-12 receptor expression prior to and prospectively during therapy to determine if downmodulation of receptors accounts for tolerance to the clinical effects of IL-12. Since our preliminary data indicate that IFN alpha upregulates IL-12 receptor expression on the peripheral blood cells of CTCL patients, we will determine if interferons in vitro can enhance IL-12 receptor expression during therapy as a potential marker of a more efficacious protocol using both IL-12 and IFN alpha. The results of these studies will further improve our understanding of the mechanisms of action of IL- 12 and other cytokines and will assist in targeting a more potent combination of agents which can suppress clonal growth and correct abnormal antitumor immunity.